Genetic Analysis of Gulf War illness: Phenotype Development, GWAS, and Gene-Environment Interaction

Veterans who served in the 1990-1991 Gulf War experience debilitating chronic symptoms at extremely high rates. In the 30 years since the Gulf War, many researchers have worked to identify the cause and biological pathway of Gulf War illness (GWI). There is, however, no biomarker, ICD code, or other standardized way to identify veterans with GWI; veterans are told they have GWI based on a clinician’s assessment of their unexplained chronic symptoms. There is also little agreement on the causes and potential biological pathways of GWI. This dissertation describes phenotyping efforts, the first genome-wide association study (GWAS) of GWI, and a candidate gene-environment interaction study. First, I describe methods for developing well-documented indicators for complex phenotypes, which have generated GWI indicators that are used for the MVP and GWECB datasets. This is the only tested and published algorithm for defining GWI. This work required extensive exploratory analysis and data cleaning, as it was the first major analysis of the GWECB dataset. The variables generated through both the data cleaning and GWI algorithm have been incorporated into the GWECB. Then, I performed the first GWAS of GWI, which supports prior work in the field and suggests further candidate analyses. Top gene-set associations include response to cadmium ion, regulation of response to interferon gamma, and regulation of autophagosome maturation. Among other top associations, these results indicate association with a neuroimmune response to exposure. GWAS summary statistics will be made available. Finally, I developed a hypothesis-driven candidate gene-environment interaction study, which replicated a previously published statistically significant association of rs662/PB pill exposure with GWI. Future research building off my contributions could help identify the underlying biological pathways and causes of GWI, allowing better treatment of the underlying disease for hundreds of thousands of Gulf War Veterans.